tbuckley/cabot-search huggingface dataset:
Validation of baseline health-related quality of life as prognostic indicator for survival outcome in men with intermediate risk prostate cancer undergoing radical prostatectomy.
Authors: Thilo Westhofen, Alexander Buchner, Boris Schlenker, Armin Becker, Christian G. Stief, Alexander Kretschmer
Journal: Journal of Clinical Oncology (2023)

340 Background: Accurate prediction of cancer outcomes remains a key component of prostate cancer (PC) treatment decision-making. Intermediate-risk PC patients represent a heterogeneous group with highly variable prognoses and it is challenging to provide uniform treatment recommendations for those patients. Previous studies have shown baseline health-related quality of life (HRQOL) to be a robust prognostic indicator for survival outcomes of different cancer entities in the metastatic setting, with scarce evidence on PC. We therefore sought to validate the predictive value of baseline HRQOL for survival outcomes in men with intermediate risk PC undergoing radical prostatectomy (RP). Methods: We identified 4780 patients with intermediate risk PC according to NCCN risk stratification and prospectively assessed baseline HRQOL prior RP. Patients were stratified by global health status (GHS) domain of the QLQ-C30 questionnaire. Oncologic endpoints were metastasis-free survival (MFS) and overall survival (OS). Multivariable Cox regression models were applied to assess the predictive value of baseline GHS on survival outcomes. Harrell's discrimination C-index was applied to calculate the predictive accuracy of the model. Decision curve analysis (DCA) was performed to validate the clinical net benefit associated with adding GHS to our multivariable model ( P &lt; .05). Results: Median follow up was 51mo. In multivariable analysis, GHS was confirmed as an independent predictor for increased MFS (HR .98, 95% CI .97-.99; P = .028) and OS (HR .97, 95% CI .95-.99; P = .008), indicating a relative risk reduction of 1.7% for MFS and 2.8% for OS per 1-point increase of baseline GHS. Adding GHS to our model improved predictive accuracy of prognosis for MFS by 6% (c-index .75 vs .72) and for OS by 8% (c-index .78 vs .74). Validation with DCA revealed a net benefit over all thresholds in prediction of MFS and OS when adding GHS to our model. Conclusions: Our findings highlight that baseline HRQOL is a valuable and robust prognostic factor for patients with intermediate-risk PC prior RP. Baseline HRQOL data improve prognostic accuracy of MFS and OS and can therefore support treatment decision-making. [Table: see text]
Detection of true positive M1 lesions by <sup>18</sup>F-rhPSMA-7.3 PET in newly diagnosed prostate cancer: Results from the phase 3 prospective LIGHTHOUSE study.
Authors: Bridget F. Koontz
Journal: Journal of Clinical Oncology (2023)

315 Background: Radiohybrid (rh) 18 F-rhPSMA-7.3 is a novel high affinity prostate specific membrane antigen (PSMA)-targeting positron emission tomography (PET) radiopharmaceutical. The LIGHTHOUSE study (NCT04186819) evaluated the diagnostic performance of 18 F-rhPSMA-7.3 in newly diagnosed prostate cancer. Here we report the 18 F-rhPSMA-7.3 verified detection rate (VDR), defined as the proportion of patients with M1 lesions identified by blinded image evaluation (BIE) and subsequently confirmed true positive (TP) by biopsy or confirmatory imaging. Methods: Men with treatment-naïve, unfavorable intermediate to very high-risk prostate cancer who were scheduled to undergo radical prostatectomy underwent PET 50-70 min after IV administration of 296 MBq 18 F-rhPSMA-7.3. Onsite readers interpreted the images before submission for BIE by 3 central readers.Ifthe onsite read indicated M1 disease, verification (by biopsy, surgery or additional imaging) of PET-positive M1 lesions was attempted prior to treatment. 18 F-rhPSMA-7.3 M1 VDR was evaluated amongall study patients without major protocol deviations. Results: Of the 335 men analyzed (median [range] PSA, 8.89 [1.15-120] ng/mL), 58 (17%) had M1 lesions by majority read. In total, 34 (10%) had verified M1 lesions with individual readers’ M1 VDR ranging from 10-15%. By region, verified M1 lesions were most common in bone, ranging from 6.0-11% across readers (majority read, 6.6%). Similar data were shown among a subgroup who had negative baseline conventional imaging. In these patients, the VDR ranged from 8.9-13% across readers (majority read, 8.6%). Again, bone showed the highest regional VDR, ranging from 4.8-9.2% (majority read, 5.1%). Conclusions: Further to its clinically meaningful sensitivity and specificity for pelvic lymph node metastases (reported separately), here we show 18 F-rhPSMA-7.3 PET to be a useful staging tool, as distant metastatic lesions were verified in 10-15% of newly diagnosed patients with unfavorable intermediate to very high-risk prostate cancer. Determining the presence of M1 disease prior to surgery may help guide treatment planning by identifying patients for whom surgery is the optimal approach, or those for whom alternatives such as radiation therapy and/or androgen deprivation may be more suitable. Clinical trial information: NCT04186819 . [Table: see text]
Machine-learning to predict utility of circulating tumor DNA (ctDNA) for somatic genotyping.
Authors: Cameron Herberts, Wilson Tu, Nicolette M. Fonseca, Corinne Maurice-Dror, Daniel Joseph Khalaf, Matti Annala, Kim N. Chi, Alexander William Wyatt
Journal: Journal of Clinical Oncology (2023)

232 Background: ctDNA genotyping is increasingly used to evaluate patient eligibility for genomics-driven treatments ( e.g., PARP inhibitors) in metastatic castration-resistant prostate cancer (mCRPC), but low ctDNA-fraction (ctDNA%) causes false negatives and is unpredictable. We investigated whether a machine-learning model exploiting routine clinical prognostic markers can predict if a mCRPC patient will have sufficient ctDNA% for informative ctDNA testing. Methods: We analysed plasma cell-free DNA (cfDNA) collected at baseline prior to first-line therapy from 463 consecutive mCRPC patients. ctDNA% was quantified using somatic allele frequencies and genome-wide copy number profiles via deep targeted sequencing. We built an XGBoost model (70:30 train-test split) using 18 clinical factors to predict synchronously measured ctDNA% (binary classification &gt;2% or ≤2%, i.e., the conventional ctDNA% limit of detection for mutations employed by commercial tests), with performance evaluated using area under the curve (AUC) of receiver operating characteristics. Results: Median age was 73 (range: 45-98) and 86% of patients had ECOG 0-1. Median ctDNA% was 5% (range: 0-89%) and correlated with serum and radiographic metrics of disease burden, including total cfDNA concentration (ng/mL of plasma, reflecting cfDNA released by both normal and tumor cells; Spearman ρ=0.55), alkaline phosphatase (ALP) per upper limit of normal (ULN) ( ρ=0.46), lactate dehydrogenase (LDH) per ULN ( ρ=0.41), PSA ( ρ=0.3), presence of liver metastases, and ≥10 bone lesions. We trained an XGBoost model incorporating these and 13 additional clinical factors achieving an AUC for ctDNA &gt;2% of 0.83 (F1 score: 0.79). SHAP interpretability scores indicated that cfDNA concentration most strongly informed prediction of ctDNA &gt;2%, followed by ALP/ULN and PSA—consistent with our prior bivariate rank correlations—whereas features associated with initial prostate cancer diagnosis (Gleason Grade Group, de novo versus metachronous M1 disease) were less informative. Recognizing that comprehensive and standardised clinical annotation is not always available in real-world settings, we built a secondary parsimonious ctDNA%-prediction tool restricted to 8 highly informative and clinically practical factors (cfDNA concentration, ALP/ULN, LDH/ULN, PSA, albumin, ECOG, liver metastases, lung metastases) and flexible to incomplete input data, achieving a comparable AUC for ctDNA&gt;2% of 0.76. Conclusions: Our results demonstrate the feasibility of a machine learning framework to estimate ctDNA% in patients with mCRPC. This point-of-care tool would enable prioritisation of mCRPC patients for ctDNA somatic genotyping with a predicted ctDNA &gt;2%, versus tissue or germline-only testing in patients with a predicted ctDNA ≤2%.
COVID-19 vaccines in patients with urothelial cancers receiving immune checkpoint inhibitors.
Authors: Danielle Gilbert, Junxiao Hu, Elaine T. Lam
Journal: Journal of Clinical Oncology (2023)

491 Background: COVID-19 vaccination recommendations for cancer patients (pts) are similar to the general population. The interaction between checkpoint inhibitors (CPI) and Sars-COV-2 vaccines has been understudied. One potential complication in pts receiving CPI is the occurrence of immune-mediated adverse events (irAEs) resulting from overactivation of the immune system. This retrospective study examined the incidence of severe irAEs in pts with bladder urothelial cancer (UC) treated with CPI therapy who received concurrent vaccinations against Sars-CoV-2. Methods: Following IRB approval, UC pts who received any approved CPI treatment since FDA authorization of the first COVID-19 vaccine in December 2020 were identified via institutional electronic health record. Pts who received 1 or more doses of an authorized vaccine within 60 days of CPI treatment were included. The primary endpoint was to evaluate the incidence of severe irAE (defined as one or more of the following: grade 3 AE or above, multi-system involvement, need for hospitalization). Secondary endpoints included time between CPI and vaccination, need for immunosuppressive therapy, and rate of discontinuation. Data was analyzed using descriptive statistics. Results: Forty pts were included in our analysis with a median age of 72.5 years (IQR: 66.0-79.2); 82% pts were male. At the time of vaccination, 37 pts (92.5%) received CPI monotherapy, 2 pts (5.0%) received combination (combo) CPI therapy, and 1 pt (2.5%) received combo platinum-based chemotherapy and CPI. The vaccine manufacturer was Pfizer Bio-N-Tech in 22 pts (55.0%), Moderna in 17 pts (42.5%), and Johnson and Johnson in 1 pt (2.5%). Number of vaccinations received was &gt;/= 3 in 27 pts, 2 in 11 pts, and 1 in 2 pts. Six pts (15.0%) experienced severe irAEs following vaccination, including nephritis, colitis, pneumonitis, DKA, and infusion-related reaction. Rates of severe irAEs were 16.2% (6/37) with CPI monotherapy, no severe irAEs occurred in the combo CPI and combo CPI-chemo groups. Severe irAEs occurred after the first vaccine dose in 1 pt (16.7%), second dose in 3 pts (50.0%), and third dose in 2 pts (33.3%) pts. The median time between CPI treatment and vaccination in this group was 22.0 days (IQR: 15.8-36.5. Hospitalization was required for all 6 patients (100%). Three pts (50.0%) required immunosuppressive therapy with a median therapy duration of 64.0 days (IQR 47.0-83.5). Five pts (83.3%) discontinued CPI therapy following severe irAEs. Conclusions: In this retrospective study, we observed a 15% rate severe irAE in UC pts receiving CPI concurrently with COVID-19 vaccines. Further investigation in pts with additional cancer types is warranted to help determine best practice guidelines for COVID-19 vaccination in cancer patients receiving CPI. NCI University of Colorado Cancer Center Support Grant 5P30CA046934-30, Health Data Compass Data Warehouse project (healthdatacompass.org).
Efficacy and safety of derazantinib (DZB) in patients with metastatic urothelial carcinoma (mUC) with activating <i>FGFR1/2/3</i> genetic aberrations (GA): Results from the phase 1b/2 FIDES-02 study.
Authors: Andrea Necchi, Tilman Todenhöfer, Jean-Laurent Deville, Manuel Häckl, Michalina Marszewska, Phil McKernan, Mikael Saulay, Marc Engelhardt, Maria De Santis
Journal: Journal of Clinical Oncology (2023)

501 Background: DZB is an oral small-molecule FGFR1/2/3 kinase inhibitor, which showed meaningful clinical benefit in cholangiocarcinoma patients (pts) with FGFR2-driven (fusions, mutations or amplifications) tumors (NCT03230318). The current study explored the activity of DZB in patients with mUC and FGFR1-3 GA (NCT04045613). Methods: Eligible pts with advanced mUC and ≥1 prior lines of standard treatment and FGFR1/2/3 mutations/short variants and rearrangements/fusions confirmed by central/local NGS testing received DZB 300 mg QD (N = 32) or 200 mg BID (N = 17). Primary efficacy endpoint was objective response rate (ORR) by central radiology review per RECIST v1.1. Key secondary efficacy endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Adverse events were assessed according to NCI CTCAE v5.0. Results: From 01/2020 to 01/2022, 282 pts were screened and 49 pts were included in the study and received DZB. The median age was 67 years, 30.6% of pts were female, 94% had an ECOG 0/1, 75.5% had ≥2 prior treatment lines, 77.6% had received prior immune-checkpoint inhibitors. At data cutoff (30-Aug-2022), all pts had discontinued treatment. Confirmed ORR was 8.2% (95% CI 2.2, 19.6) based on 4 PRs (all with FGFR3 S249C mutation/ FGFR3 TACC3 fusion) and the DCR was 28.6% (95%CI: 16.6, 43.3). PFS ranged 0.3-8.8 months, and OS ranged 0.3-21.4 months. Median duration of response was 6.9 months, and longest time on treatment was 18 months. Most common all-grade treatment-emergent adverse events were transaminase increased (40.8%), nausea (38.8%), fatigue (32.7%) and decreased appetite (30.6%). Drug-related retinal events (12.2%), nail toxicities (6.1%), stomatitis (4.1%) and palmar-plantar erythrodysesthesia (PPE) (0%) were infrequent. Safety and efficacy results were similar in patients receiving 300 mg QD or 200 mg BID. Conclusions: Derazantinib showed signals of clinical activity in some patients with mUC and FGFR1-3 GA but the observed ORR and PFS did not meet contemporary benchmarks that would support further clinical development of derazantinib as monotherapy in this indication. Derazantinib showed a well-manageable safety profile with low rates of hand-foot syndrome, stomatitis, nail toxicity and retinal side effects. Clinical trial information: NCT04045613 .
Prognostic value of circulating cell-free DNA in association with choriocarcinoma syndrome development in patients with germ cell tumors.
Authors: Katarina Rejlekova, Peter Celec, Barbora Vlkova, Katarina Kalavska, Nikola Hapakova, Marek Makovnik, Michal Chovanec, Valentina De Angelis, Jana Obertova, Patrik Palacka, Zuzana Sycova-Mila, Jozef Mardiak, Michal Mego
Journal: Journal of Clinical Oncology (2023)

424 Background: Germ cell tumors (GCTs) represent a highly curable malignancy; however, a small portion of patients can develop choriocarcinoma syndrome (CS) connected with acute respiratory distress syndrome (ARDS) with high mortality rate shortly after the chemotherapy start. The aim of this study was to assess the prognostic value of circulating cell-free – extracellular DNA (ecDNA) in patients with GCTs and its association with CS development and outcome. Methods: This study included 23 patients with poor-prognosis GCTs treated from November 2002 to May 2018 at the National Cancer Institute in Slovakia. Pre-treatment total ecDNA, nuclear (ncDNA) and mitochondrial DNA (mtDNA) were quantified in plasma using fluorometry and real-time PCR and analyzed in association with CS development and survival. Results: Four (17%) patients developed CS and all of them died due to ARDS shortly after the chemotherapy start. Total ecDNA, but not ncDNA or mtDNA were associated with CS development. Four out of 11 (37%) patients with high plasma ecDNA developed CS compared to 0 out of 12 (0%) patients with low plasma ecDNA (p = 0.037). In univariate analysis, higher concentration of ecDNA also positively correlated with ECOG PS ≥2, metastatic lung involvement ≥50%, weight loss ≥10%, hemoglobin ≤100 g/l, and neutrophil to lymphocyte ratio ≥ 3.3 at the time of presentation. Patients with low ecDNA had significantly better PFS (HR = 0.35, 95% CI 0.11-1.17, p = 0.043) and OS (HR = 0.26, 95% CI 0.06-1.20, p = 0.032) compared to patients with high pretreatment concentration of ecDNA. Conclusions: In this study we have proved that quantitative analysis of plasma ecDNA has prognostic value for CS development in patients treated due to GCTs. Further research focused on the biology of ecDNA may help us to understand its role as a biomarker, but also a potentially treatable pathogenic factor for choriocarcinoma syndrome development.
Short term pathologic outcomes and biochemical recurrence rates of single port transvesical retzius-sparing radical prostatectomy as compared to multiport radical prostatectomy.
Authors: Tarik Benidir, Ethan Ferguson, Zaeem M Lone, Rebecca Campbell, Christopher J. Weight, Jihad Kaouk
Journal: Journal of Clinical Oncology (2023)

369 Background: Single port radical prostatectomy with a transvesical Retzius-sparing approach (SPRP) has shown technical feasibility and early evidence of improved time to urinary continence. How this novel approach leads to differences in pathologic outcomes and biochemical recurrence rates (BCR) as compared to multiport radical prostatectomy (MPRP) has yet to be investigated. Our goal was thus to study the pathologic and short term survival outcomes of patients undergoing SPRP as compared to those undergoing MPRP. Methods: Single center, single surgeon retrospective review of prospectively collected data on 169 patients with low and intermediate risk prostate cancer, whom either underwent SPRP or MRPR (2017-2022). Preoperative clinicopathologic and radiographic characteristics were compared. Following RP, pathologic outcomes, including T stage, grade group (GG), margin status, extraprostatic extension (EPE), seminal vesical invasion (SVI), node retrieval rates, lymph node invasion (LNI) and other adverse histopathologic features were compared between both groups. Cox proportional hazards univariate analysis was used to evaluate the impact of SPRP on biochemical recurrence free survival as compared to MPRP with a three year follow up. Results: A total of 84 patients underwent MPRP and 85 patients underwent SPRP. The SPRP cohort had a higher proportion of clinical T stage one as compared to the MPRP cohort (99% vs 85%, p=0.04), however both groups did not differ preoperatively in terms of median total PSA (6.9 MPRP vs 6.2 SPRP, p=0.24), PI-RADS score (p=0.60) or biopsy GG (p=0.52). Following RP, both groups had similar pathologic outcomes including final grade group, T stage, EPE rates, SVI and Cribriform/intraductal rates (p&gt;0.05). SPRP did yield a lower median number of nodes as compared to MPRP (2 (0-5) vs 6(4-9), p&lt;0.001), but this did not translate to differences in LNI (p=0.08). At a median of approximately 12 months of follow up, there were no differences in the biochemical recurrence-free survival rates among both groups (p=0.38). Cox proportional hazards univariate analysis did not consider SPRP to be an independent predictor of biochemical recurrence (HR 0.53, 95% CI 0.13-2.23, p=0.39). Conclusions: In well selected men, SPRP yields similar short term oncologic control as MPRP with equal rates of margin status, EPE/SVI invasion rates and rates of biochemical recurrence at 1 year. In this small, early, single surgeon experience, SPRP appears to be oncologically safe for low and intermediate risk prostate cancer patients, however longer follow up is necessary, larger numbers and multi- institutional comparisons are needed.
The predictive value of hematological markers in renal cell carcinoma.
Authors: Omar Al Ta'ani, Osama Abu-Shawer, Saja Jamil Abdelhadi, Murad Alkderat, Hala Sultan, Hebah Alshahwan, Diya' Maher Y Safi, Ibrahim Abuelbeh, Mohannad Maher Y Safi, Maysa Al-Hussaini
Journal: Journal of Clinical Oncology (2023)

621 Background: Renal cell carcinoma (RCC), which accounts for about 3% of adult malignancies, is regarded as a major cause of morbidity and mortality. The neutrophil-lymphocyte ratio (NLR) is a simple, reliable, and cost-effective biomarker of systemic inflammation that has been linked to oncologic outcomes in a variety of malignancies. The objective of this study is to determine whether NLR, along with other hematological parameters such as absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute eosinophil count (AEC), absolute monocyte count (AMC), monocyte-lymphocyte ratio (MLR), platelet-lymphocyte ratio (PLR), and the Systemic Immune-Inflammation Index (SII; defined as neutrophils counts X platelets counts divided by lymphocyte count), are related to baseline distant metastases and overall survival (OS) in RCC patients. Methods: Clinical data from 203 RCC patients treated at King Hussein Cancer Center (Amman, Jordan) were retrospectively reviewed. We examined the relationship between age, sex, ANC, AMC, ALC, AEC, NLR, MLR, PLR, and SII with baseline distant metastasis and patients’ OS. Results: Of the 203 patients, 97 patients (48.5%) were stage 4 at the time of diagnosis. Univariate analysis showed that patients with high baseline ANC (&gt;5400), AMC (&gt;600), AEC (&gt;120), NLR (&gt;4.36), MLR (&gt;0.33), PLR (&gt;140.44), WBC count (&gt;8.2), SII (&gt;757.7) and low baseline ALC (≤1900) had more baseline metastasis. (p-value: &lt;0.001, 0.007, 0.020, &lt;0.001, &lt;0.001, &lt;0.001, 0.006, &lt;0.001, and 0.004, respectively). On multivariate analysis, patients who had elevated NLR (&gt;4.36) were more likely to have distant metastasis at the time of diagnosis (p-value = 0.0076, odds ratio (OR): 4.45, CI: 1.49–13.33). Moreover, univariate and multivariate analysis showed that patients with elevated NLR (&gt;4.36) were associated with poorer OS (p-value: &lt;0.0001 and 0.0065, respectively). In addition, patients with elevated baseline ANC, AMC, MLR, PLR, SII, WBC count, and low ALC values were associated with poorer OS (p-value: &lt;0.0001, 0.0234, &lt;0.0001, &lt;0.0001, &lt;0.0001, 0.0290, and &lt;0.0001, respectively). Conclusions: The results of this study indicate a substantial correlation between several hematological parameters, including NLR, with the presence of distant metastases at the time of diagnosis and OS. Further research is required to uncover whether these hematological markers may be used to identify patients who are more likely to develop metastases and predict treatment response.